Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor

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Title
Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor
Author(s)
Won-Kyung Cho; Y R Seong; Y H Lee; M J Kim; Kyung Sun Hwang; Jin Sang Yoo; See Young Choi; Cho Rok Jung; Dong Soo Im
Bibliographic Citation
Molecular Therapy, vol. 10, no. 5, pp. 938-949
Publication Year
2004
Abstract
Solid tumors contain normoxic and hypoxic regions depending on the distance from the capillary. Normal cells may also be exposed to hypoxia under certain physiological conditions. Tumor hypoxia has been shown to associate strongly with tumor propagation and malignant progression. Hypoxia-inducible factor (HIF)-1α is stable under hypoxia and induces transcription of target genes by binding to the hypoxia-response element (HRE). Here we investigated the oncolytic effects of a novel adenovirus mutant with a deleted E1B55 gene (Ad.δ55.HRE), in which the expression of E1A, which is essential for adenoviral replication, is regulated under the control of an HRE-expression system. Ad.δ55.HRE expressed E1A under normoxia and more E1A under hypoxia and exhibited oncolytic effects on various cultured tumor cells, but its cytotoxic effect is relatively attenuated in normal fibroblast cells under normoxic and hypoxic conditions. Ad.δ55.HRE lysed Huh-7 hepatoma cells stably expressing HIF-1α more effectively compared to parental cells. Ad.δ55.HRE treatment exhibited significant antitumor activity in PC-3 prostate- and MDA-MB-435 breast tumor-bearing nude mice in which HIF-1α protein was immunohistochemically detected. The E1A and hexon proteins of adenovirus were immunostained in MDA-MB-435 xenografts after Ad.δ55.HRE treatment, suggestive of viral replication. Our results suggest that Ad.δ55.HRE may be useful for the treatment of solid tumors.
Keyword
AdenovirusHypoxiaOncolyticTumor
ISSN
1525-0016
Publisher
Elsevier-Cell Press
DOI
http://dx.doi.org/10.1016/j.ymthe.2004.07.023
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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